Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM5PP3BP4_StrongBP6_Very_StrongBS1BS2

The NM_019098.5(CNGB3):c.1397T>C(p.Met466Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00166 in 1,614,042 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M466K) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0091 ( 19 hom., cov: 32)

Exomes 𝑓: 0.00088 ( 15 hom. )

Consequence

CNGB3
NM_019098.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:6

Conservation

PhyloP100: 9.32

Publications

13 publications found

Variant links:

Genes affected

CNGB3 (HGNC:2153): (cyclic nucleotide gated channel subunit beta 3) This gene encodes the beta subunit of a cyclic nucleotide-gated ion channel. The encoded beta subunit appears to play a role in modulation of channel function in cone photoreceptors. This heterotetrameric channel is necessary for sensory transduction, and mutations in this gene have been associated with achromatopsia 3, progressive cone dystrophy, and juvenile macular degeneration, also known as Stargardt Disease. [provided by RefSeq, Feb 2010]

CNGB3 Gene-Disease associations (from GenCC):

achromatopsia 3
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
CNGB3-related retinopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
cone dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
achromatopsia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
severe early-childhood-onset retinal dystrophy
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

CNGB3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr8-86629002-A-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 427675.Status of the report is no_assertion_criteria_provided, 0 stars.

PP3

Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_noAF, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.012754291).

BP6

Variant 8-86629002-A-G is Benign according to our data. Variant chr8-86629002-A-G is described in ClinVar as Benign. ClinVar VariationId is 261083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00913 (1390/152282) while in subpopulation AFR AF = 0.0316 (1315/41570). AF 95% confidence interval is 0.0302. There are 19 homozygotes in GnomAd4. There are 677 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 19 AR,AD,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019098.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNGB3	NM_019098.5	MANE Select	c.1397T>C	p.Met466Thr	missense	Exon 12 of 18	NP_061971.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CNGB3	ENST00000320005.6	TSL:1 MANE Select	c.1397T>C	p.Met466Thr	missense	Exon 12 of 18	ENSP00000316605.5
CNGB3	ENST00000681546.1		n.1217T>C		non_coding_transcript_exon	Exon 7 of 13
CNGB3	ENST00000681746.1		n.1397T>C		non_coding_transcript_exon	Exon 12 of 19	ENSP00000505959.1

Frequencies

GnomAD3 genomes

AF:

0.00915

AC:

1392

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0318

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00380

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00623

GnomAD2 exomes

AF:

0.00225

AC:

566

AN:

251056

AF XY:

0.00162

show subpopulations

Gnomad AFR exome

AF:

0.0317

Gnomad AMR exome

AF:

0.00107

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.000816

GnomAD4 exome

AF:

0.000880

AC:

1287

AN:

1461760

Hom.:

Cov.:

AF XY:

0.000747

AC XY:

543

AN XY:

727178

show subpopulations

African (AFR)

AF:

0.0331

AC:

1108

AN:

33468

American (AMR)

AF:

0.00119

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.000128

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000126

AC:

AN:

1111932

Other (OTH)

AF:

0.00162

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

157

235

314

392

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

152

190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00913

AC:

1390

AN:

152282

Hom.:

Cov.:

AF XY:

0.00909

AC XY:

677

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.0316

AC:

1315

AN:

41570

American (AMR)

AF:

0.00380

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68034

Other (OTH)

AF:

0.00617

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

131

196

262

327

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00271

Hom.:

Bravo

AF:

0.0103

ESP6500AA

AF:

0.0320

AC:

141

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00255

AC:

310

Asia WGS

AF:

0.000289

AC:

AN:

3476

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Achromatopsia 3 (2)

not provided (2)

Achromatopsia (1)

not specified (1)

Severe early-childhood-onset retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Benign

-0.062

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.59

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.86

MetaRNN

Benign

0.013

MetaSVM

Uncertain

0.40

MutationAssessor

Pathogenic

3.8

PhyloP100

9.3

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-6.0

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.030

Polyphen

0.99

Vest4

0.97

MVP

1.0

MPC

0.19

ClinPred

0.083

GERP RS

5.9

Varity_R

0.82

gMVP

0.95

Mutation Taster

=56/44

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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rs35010099

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over